The long-term objectives of the proposed research will be will be to gain insight into the involvement of sphingolipids in the etiology of obesity. These studies will use Drosophila as a model genetic organism to examine the mechanisms that underlie the development of obese characteristics when genes that regulate sphingolipid metabolism are disrupted. Six specific aims are proposed: (1) The expression profiles of genes encoding key enzymes that regulate sphingolipid metabolism will be mapped in adult flies. (2) Genetic models that systematically disrupt sphingolipid metabolism and cause obesity will be created. (3) Lipid profiles of sphingolipids, triglycerides and cholesterol will be generated in sphingolipid metabolic mutant and transgenic fly lines. (4) Obesity phenotypes of sphingolipid metabolic mutants and transgenic organisms will be characterized (5) Regulation of the fatty acid biosynthetic pathway via SREPB processing will be examined. (6) Genetic screens will be performed to identify novel genes involved in the development of obesity and modifiers of obesity phenotypes in sphingolipid metabolic mutants. It is anticipated that the proposed studies will form a firm and novel foundation for understanding the relationships between sphingolipid metabolism and obesity and may uncover novel regulatory mechanisms that govern these pathways.